Project Summary/Abstract Pulmonary diseases involving obstructive, interstitial, and vascular pathologies account for more than $180 billion annual U.S. healthcare costs. A major bottleneck preventing reversal of this trend is lack of sufficiently sensitive and reliable tools to diagnose and phenotype disease, and optimize treatment. Hyperpolarized 129Xe gas MRI is emerging as a promising solution for non-invasive 3D imaging of pulmonary function?now in Phase III clinical trials for ventilation MRI, with research underway to extend it to image pulmonary gas exchange. This new frontier offers sensitivity to pathology associated with emphysematous, interstitial, or vascular disease processes. We can now use 129Xe MRI to quantify regional impairment related to these conditions. But, lung pathology rarely presents as one isolated condition; patients frequently suffer multiple disease processes simultaneously. We intend to disentangle these phenomena through comprehensive studies in human subjects and animal models to not only quantify gas-exchange impairment, but identify its underlying cause. Our long-term goal is to develop a time- and cost-efficient, non-invasive MRI exam to quantify the relative burdens of emphysematous, interstitial, and vascular pulmonary functional impairment. Our approach exploits our unique experiences in pioneering both preclinical and clinical 129Xe MR imaging, as well as quantitative analysis of gas exchange. The objective of this study is to advance methodology for 129Xe gas exchange MRI acquisition and analysis, while conducting the preclinical and clinical studies needed to identify unique signatures of underlying pathologies. Our central hypothesis is that by deploying and optimizing a comprehensive protocol that includes exchange imaging and spectroscopy, in animal models, healthy volunteers, and patients, the key signatures of disease will be identified. The rationale for the proposed research is that more precise diagnostic information is critical to help clinicians make accurate and timely therapy decisions. Thus, the work is relevant to that part of the NIH Mission that pertains to improving health by developing and accelerating biomedical technologies. Guided by strong preliminary data, our approach is based on four Specific Aims: 1) Double SNR and CNR for 129Xe gas exchange (GX) MRI maps; 2) Characterize GX MRI in rodent models of emphysema, fibrosis, and pulmonary hypertension (PH); 3) Quantify GX MRI in patients with COPD and PH; and 4) Monitor GX MRI changes before and after radiation therapy. These aims will 1) position GX MRI for multi-center deployment, 2) establish a clear link between GX MRI features and pathology, and 3) identify characteristic spectroscopic and image patterns in emphysematous, interstitial, and vascular disease. The approach is innovative because it exploits the unique solubility and chemical shift of 129Xe and sophisticated encoding to measure features in well-characterized animal models and patients across a broad spectrum of diseases. The research is significant because it drives us towards a single, non-invasive 3D functional imaging modality that can characterize and quantify underlying pathology in a single breath.